The general aim of this project is study the effects of immunotoxin induced transient T-cell depletion on the modulation of T cells from immunization responses towards tolerizing responses, and to use this knowledge for the experimental and clinical treatment of T cell driven autoimmune diseases, graft-versus-host disease, and the induction of tolerance to mismatched organ transplants. A 2-3 day course of anti-rhesus CD3 immunotoxin constructed with CRM9, a binding site mutant of diphtheria toxin, depletes lymph node and blood T cells by 99% without systemic toxicity. This process is associated with a marked prolongation of survival of mismatched functioning rhesus kidney transplants and the induction of long term tolerance in over 50% of the cases without further immunosuppressive therapy. Although tolerance has previously been achieved in rodents, it has not been previously achieved in primates at acceptable levels of immunosuppression. Experimental allergic encephalomyelitis (EAE), a T cell driven autoimmune disease, has been moderated by anti-CD3 immunotoxin. Monkeys were treated after white blood cells entered the CSF. EAE in non-treated control monkeys progressed rapidly and paralysis occurred 4-6 days after CSF pleocytosis. Histopathology showed numerous large inflammatory plaques throughout brain containing macrophages and T cells. In monkeys treated at the time of pleocytosis paralysis was either delayed or never occurred. Histopathology revealed few inflamatory plaques that were notable for their low or absent T cell content. Although T cells repopulate in the periphery post-treatment, they do not return to the CNS in large numbers, suggesting that the newly repopulated T cells have lost their previously acquired CNS homing capability. This immunotoxin may be useful in treating CNS autoimmune diseases such as multiple sclerosis.